title: Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism.
abstract: Antibody-maytansinoid conjugates (AMCs) are targeted chemotherapeutic agents consisting of a potent microtubule-depolymerizing maytansinoid (DM1 or DM4) attached to lysine residues of a monoclonal antibody (mAb) using an uncleavable thioether linker or a stable disulfide linker. Most of the administered dose of an antibody-based therapeutic is slowly catabolized by the liver and other tissues of the reticuloendothelial system. Maytansinoids released from an AMC during this catabolic process could potentially be a source of toxicity. To investigate this, we isolated and identified liver metabolites in mice for three different [(3)H]AMCs with structures similar to those currently undergoing evaluation in the clinic. We then synthesized each metabolite to confirm the identification and assessed their cytotoxic potencies when added extracellularly. We found that the uncleavable mAb-SMCC-[(3)H]DM1 conjugate was degraded to a single major maytansinoid metabolite, lysine-SMCC-[(3)H]DM1, that was nearly 50-fold less cytotoxic than maytansine. The two disulfide-linked conjugates, mAb-SPP-[(3)H]DM1 and mAb-SPDB-[(3)H]DM4, were also found to be catabolized to the analogous lysine-linked maytansinoid metabolites. However, subsequent reduction, S-methylation, and NADPH-dependent oxidation steps in the liver yielded the corresponding S-methyl sulfoxide and S-methyl sulfone derivatives. The cytotoxic potencies of the oxidized maytansinoids toward several human carcinoma cell lines were found to be 5- to 50-fold less potent than maytansine. Our results suggest that liver plays an important role in the detoxification of both cleavable and uncleavable AMCs.
authors.affiliation: ImmunoGen, Inc. , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Sun
authors.forename: Wayne
authors.initials: W
authors.lastname: Widdison
authors.forename: Michele
authors.initials: M
authors.lastname: Mayo
authors.forename: Sharon
authors.initials: S
authors.lastname: Wilhelm
authors.forename: Barbara
authors.initials: B
authors.lastname: Leece
authors.forename: Ravi
authors.initials: R
authors.lastname: Chari
authors.forename: Rajeeva
authors.initials: R
authors.lastname: Singh
authors.forename: Hans
authors.initials: H
authors.lastname: Erickson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008453:Maytansine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure
chemical_list: D000911:Antibodies, Monoclonal; D008453:Maytansine